This project studies risk and protective factors for the very high risk of schizophrenia in chromosome 22q11.2 deletion syndrome (22q), a disorder with a clear genetic etiology but with a complex and variable phenotype. It takes advantage of the unique nature of the 22q population, which has a genetically conferred high risk for schizophrenia yet also provides the rare opportunity for long range prospective developmental studies. Recognizing that, in a population where up to 30% of those affected will develop schizophrenia, 70% with chromosome 22q11.2 deletions do not, the proposed research studies the factors influencing psychosis risk and protection by taking a novel neurodevelopmental approach. It does so in a number of innovative ways that complement existing studies in 22q. Primarily, it asks how prevalent neurocognitive impairment in this disorder creates and interacts with stress and anxiety to affect risk for or protection against the development of psychosis-proneness, before the onset of schizophrenia. Psychosis-proneness will be measured with a novel combination of categorical and dimensional assays of attenuated psychotic symptoms that will be developed by leaders in the field. Our core hypothesis is that psychosis-proneness in 22q, as well as in idiopathic Sz, is developmentally modulated by several critical factors that interact to alter mental health outcomes. Primary is degree of neurocognitive deficit, particularly in executive function and attention. Impairment levels moderate degree of challenge and associated affective states. Cognitive-affective processes interact with variable stress reactivity which in turn, affects anxiety and adaptive function, further moderating the challenge that is experienced. Using a longitudinal cohort-sequential design, novel for 22q, we study how neurocognition, affect, stress and anxiety, interact to alter psychosis-proneness in 22q. We do so by examining the trajectory of a latent construct in individuals aged 12-21 years, each assessed 2-3 times during a 5 year period, to generate and test predictors of psychosis-proneness severity. Based on a model that links neurocognitive and affective processes to explain psychopathology, the proposed research combines cognitive performance and functional neuroimaging data using Event Related Potentials in emotionally hot and cold task variants with measures of stress hormones and anxiety and adaptive function. Along with structural and functional imaging of neural connectivity these measures provide the variables that will be subjected to factor analysis in order to create, from our latent risk/protection construct, specific predictors of degree of psychosis-proneness captured by our novel outcome measure. The relative weights of these predictors will indicate the power of each to identify specific domains of neurobiological functioning that can be further tested as biomarkers of risk and protection, for those with and without 22q. Those same domains will also be targets for identifying or developing validated, evidence-based therapies that can further reduce risk for psychosis.